Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

Abstract

Aims/hypothesis. Glucokinase plays a key role in glucose homeostasis and the expression of its gene is differentially regulated in pancreatic beta cells and in the liver through distinct promoters. The factors that determine the tissue-specific expression of the glucokinase gene are not known. Putative binding sites for hepatocyte nuclear factor (HNF)-6, the prototype of the ONECUT family of transcription factors, are present in the hepatic promoter of the glucokinase gene and in diabetic hnf6 knockout mice. We hypothesized that HNF-6 controls the activity of the hepatic glucokinase promoter. Methods. We tested the binding of recombinant HNF-6 to DNA sequences from the mouse hepatic glucokinase promoter in vitro and the effect of HNF-6 on promoter activity in transfected cells. We investigated in vivo the role of HNF-6 in mice by examining the effect of inactivating the hnf6 gene on glucokinase gene-specific deoxyribonuclease I hypersensitive sites in liver chromatin and on liver glucokinase mRNA concentration.Results. HNF-6 bound to the hepatic promoter of the glucokinase gene and stimulated its activity. Inactivation of the hnf6 gene did not modify the pattern of deoxyribonuclease I hypersensitive sites but was associated with a decrease of liver glucokinase mRNA to half the control value. Conclusions/interpretation. Although HNF-6 is not required to open chromatin of the hepatic promoter of the glucokinase gene, it stimulates transcription of the glucokinase gene in the liver. This could partly explain the diabetes observed in hnf6 knockout mice.

Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability

“…We previously observed increased liver glycogen content in Oc1 heterozygous (OH) and DH mice at P21 because of Oc1 heterozygosity, in agreement with the role of Oc1 in hepatic glycogen breakdown (34,58,60). Thus, another possible explanation for the reduced blood glucose levels in DH at P14 was an increase in liver glycogen.…”

“…6F). We had previously observed that DH mice had normal glucose tolerance at weaning likely because of increased liver glycogen content (26), which we hypothesized is the result of the known role of Oc1 regulation of genes involved in glycogenolysis in the liver (34,58,60). In looking at the livers from 3-mo-old animals, we observed that PH livers had reduced glycogen content compared with controls (Fig.…”

Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6

“…Null mice with global disruption of Hnf6 have aberrant hepatoblast maturation, abnormal bile duct formation and die early of cholestasis [3]. In the differentiated liver, Hnf6 regulates hepatocyte target genes involved in metabolic [4] [5] [6] and regenerative functions [7] [8]. We previously treated mice with recombinant human GH to increase in vivo Hnf6 expression and found that GH treatment improved bile duct ligation (BDL) hepatic injury, enhanced cholesterol clearance and improved hepatocyte-specific cellular proliferation [8].…”

Is Environmental Cadmium Exposure Causally Related to Diabetes and Obesity?

“…PFKFB4 expression is regulated by the hepatocyte nuclear factor-6 (Hnf-6) [ 234 ] and diabetes developed in Hnf6-knockout mice [ 235 ]. PFKFB4 protein phosphorylation, mediated by the cAMP dependent protein kinase A (PKA) reduced F-2,6-P 2 level in the liver, thereby increasing gluconeogenesis with concomitantly reducing glycolysis [ 236 ].…”